{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:04:17Z","timestamp":1792458257880,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been shown to provide extra-glycemic advantages, such as cardiovascular and renal protection, in the treatment of type 2 diabetic mellitus (T2DM). Recent data points to the possibility that gut microbiota modification may contribute to their beneficial impact. This review examines changes in microbial composition, metabolite synthesis (such as short-chain fatty acids (SCFA), bile acids, and endotoxins), and their systemic implications by integrating clinical and preclinical data on the interactions between various drug types and the gut microbiota. GLP-1RAs may favor certain taxa that synthesize SCFA and Akkermansia muciniphila. This may improve insulin sensitivity and lower inflammation. Likewise, SGLT-2is may favor a eubiotic state, which is associated with better renal and metabolic outcomes. We also discuss the use of baseline microbial profiles to predict therapy responses in a microbiota-informed precision medicine approach. Larger human investigations are required to explore causality and therapeutic efficacy, as mechanistic insights are still limited despite early encouraging findings. This narrative review synthesizes both clinical and preclinical data identified through PubMed, Scopus, Web of Science, Embase, and Google Scholar up to May 2025. Personalized holistic T2DM therapy plans that integrate both host and microbial pathways may be made possible by gut microbiota studies.<\/jats:p>","DOI":"10.1093\/ckj\/sfaf351","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T12:42:12Z","timestamp":1763124132000},"source":"Crossref","is-referenced-by-count":23,"title":["Gut microbiota modulation in GLP-1RA and SGLT-2i therapy: clinical implications and mechanistic insights in type 2 diabetes"],"prefix":"10.1093","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-0675","authenticated-orcid":false,"given":"Mehmet","family":"Kanbay","sequence":"first","affiliation":[{"name":"Division of Nephrology, Koc University School of Medicine Department of Internal Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Al-Shiab","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ermeena","family":"Shah","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasin","family":"Ozbek","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Guldan","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-9523","authenticated-orcid":false,"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD Department of Nephrology and Hypertension, , UAM), Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Fouque","sequence":"additional","affiliation":[{"name":"HCL-Lyon Sud Hospital, Univ. Claude Bernard Lyon Department of Nephrology-Nutrition-Dialysis, , Pierre B\u00e9nite ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"2025121604015400100_bib1","doi-asserted-by":"publisher","first-page":"905171","DOI":"10.3389\/fendo.2022.905171","article-title":"Effects of oral glucose-lowering agents on gut microbiota and microbial metabolites","volume":"13","author":"Wang","year":"2022","journal-title":"Front Endocrinol"},{"key":"2025121604015400100_bib2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s40200-024-01435-1","article-title":"The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review","volume":"23","author":"Afsar","year":"2024","journal-title":"J Diabetes Metab Disord"},{"key":"2025121604015400100_bib3","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.3389\/fmicb.2017.01765","article-title":"Next-generation beneficial microbes: the case of Akkermansia muciniphila","volume":"8","author":"Cani","year":"2017","journal-title":"Front Microbiol"},{"key":"2025121604015400100_bib4","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nrendo.2015.128","article-title":"Short-chain fatty acids in control of body weight and insulin sensitivity","volume":"11","author":"Canfora","year":"2015","journal-title":"Nat Rev Endocrinol"},{"key":"2025121604015400100_bib5","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.ebiom.2018.11.046","article-title":"Bi-directional drug-microbiome interactions of anti-diabetics","volume":"39","author":"Whang","year":"2019","journal-title":"EBioMed"},{"key":"2025121604015400100_bib6","doi-asserted-by":"publisher","first-page":"853771","DOI":"10.3389\/fcimb.2022.853771","article-title":"Gut microbiota and antidiabetic drugs: perspectives of personalized treatment in type 2 diabetes mellitus","volume":"12","author":"Liu","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"2025121604015400100_bib7","doi-asserted-by":"publisher","DOI":"10.3390\/nu9050489","article-title":"Nutrients turned into toxins: microbiota modulation of nutrient properties in chronic kidney disease","volume":"9","author":"Fernandez-Prado","year":"2017","journal-title":"Nutrients"},{"key":"2025121604015400100_bib8","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1126\/science.aao5774","article-title":"Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes","volume":"359","author":"Zhao","year":"2018","journal-title":"Science"},{"key":"2025121604015400100_bib9","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.3748\/wjg.v30.i43.4682","article-title":"Interplay of gut microbiota, glucagon-like peptide receptor agonists, and nutrition: new frontiers in metabolic dysfunction-associated steatotic liver disease therapy","volume":"30","author":"Guney-Coskun","year":"2024","journal-title":"World J Gastroenterol"},{"key":"2025121604015400100_bib10","doi-asserted-by":"publisher","first-page":"9167","DOI":"10.1038\/s41598-021-88612-x","article-title":"Effects of GLP-1 receptor agonist on changes in the gut bacterium and the underlying mechanisms","volume":"11","author":"Kato","year":"2021","journal-title":"Sci Rep"},{"key":"2025121604015400100_bib11","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","article-title":"Glucagon-like peptide-1 receptor: mechanisms and advances in therapy","volume":"9","author":"Zheng","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"2025121604015400100_bib12","doi-asserted-by":"publisher","DOI":"10.3390\/genes8100250","article-title":"Effects of antidiabetic drugs on gut microbiota composition","volume":"8","author":"Montandon","year":"2017","journal-title":"Genes"},{"key":"2025121604015400100_bib13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21114113","article-title":"Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease","volume":"21","author":"Martinez-Moreno","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2025121604015400100_bib14","doi-asserted-by":"publisher","first-page":"116203","DOI":"10.1016\/j.bcp.2024.116203","article-title":"Butyrate promotes kidney resilience through a coordinated kidney protective response in tubular cells","volume":"224","author":"Favero","year":"2024","journal-title":"Biochem Pharmacol"},{"key":"2025121604015400100_bib15","doi-asserted-by":"publisher","DOI":"10.3390\/toxins10070300","article-title":"Impact of altered intestinal microbiota on chronic kidney disease progression","volume":"10","author":"Castillo-Rodriguez","year":"2018","journal-title":"Toxins"},{"key":"2025121604015400100_bib16","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-334634","article-title":"Toxic microbiome and progression of chronic kidney disease: insights from a longitudinal CKD-Microbiome study","author":"Laiola","year":"2025","journal-title":"Gut"},{"key":"2025121604015400100_bib17","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of action and therapeutic application of glucagon-like peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab"},{"key":"2025121604015400100_bib18","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10102061","article-title":"GLP-1 and GLP-2 orchestrate intestine integrity, gut microbiota, and immune system crosstalk","volume":"10","author":"Abdalqadir","year":"2022","journal-title":"Microorganisms"},{"key":"2025121604015400100_bib19","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1111\/dom.12748","article-title":"Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients","volume":"18","author":"Smits","year":"2016","journal-title":"Diabetes Obes Metab"},{"key":"2025121604015400100_bib20","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/j.cmet.2017.04.013","article-title":"A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism","volume":"25","author":"Grasset","year":"2017","journal-title":"Cell Metab"},{"key":"2025121604015400100_bib21","doi-asserted-by":"publisher","first-page":"2274124","DOI":"10.1080\/19490976.2023.2274124","article-title":"Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling","volume":"15","author":"Wang","year":"2023","journal-title":"Gut Microbes"},{"key":"2025121604015400100_bib22","doi-asserted-by":"publisher","first-page":"114830","DOI":"10.1016\/j.celrep.2024.114830","article-title":"Gut Bacteroides ovatus ameliorates renal fibrosis by promoting the production of HDCA through upregulation of Clostridium scindens","volume":"43","author":"Si","year":"2024","journal-title":"Cell Rep"},{"key":"2025121604015400100_bib23","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.3389\/fendo.2021.814770","article-title":"Gut microbial signatures for glycemic responses of GLP-1 receptor agonists in type 2 diabetic patients: a pilot study","volume":"12","author":"Tsai","year":"2022","journal-title":"Front Endocrinol"},{"key":"2025121604015400100_bib24","doi-asserted-by":"publisher","first-page":"101223","DOI":"10.1016\/j.diabet.2021.101223","article-title":"Liraglutide and sitagliptin have no effect on intestinal microbiota composition: a 12-week randomized placebo-controlled trial in adults with type 2 diabetes","volume":"47","author":"Smits","year":"2021","journal-title":"Diabetes Metab"},{"key":"2025121604015400100_bib25","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.109784","article-title":"Correlation between intestinal flora and GLP-1 receptor agonist dulaglutide in type 2 diabetes mellitus treatment\u2014a preliminary longitudinal study","volume":"27","author":"Liang","year":"2024","journal-title":"iScience"},{"key":"2025121604015400100_bib26","doi-asserted-by":"publisher","DOI":"10.3390\/nu17081303","article-title":"Effects of GLP-1 analogues and agonists on the gut microbiota: a systematic review","volume":"17","author":"Gofron","year":"2025","journal-title":"Nutrients"},{"key":"2025121604015400100_bib27","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.1016\/j.kint.2023.10.018","article-title":"Kidney Disease: Improving Global Outcomes CKDWG. KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease","volume":"105","year":"2024","journal-title":"Kidney Int"},{"key":"2025121604015400100_bib28","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1161\/CIRCULATIONAHA.116.021887","article-title":"Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications","volume":"134","author":"Heerspink","year":"2016","journal-title":"Circulation"},{"key":"2025121604015400100_bib29","doi-asserted-by":"publisher","first-page":"113677","DOI":"10.1016\/j.biopha.2022.113677","article-title":"Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: a clinical and experimental study","volume":"154","author":"Mora-Fernandez","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"2025121604015400100_bib30","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.2337\/dc16-0330","article-title":"CV protection in the EMPA-REG OUTCOME trial: a \u201cthrifty substrate\u201d hypothesis","volume":"39","author":"Ferrannini","year":"2016","journal-title":"Diabetes Care"},{"key":"2025121604015400100_bib31","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1002\/bdd.1909","article-title":"SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria","volume":"35","author":"Chino","year":"2014","journal-title":"Biopharm Drug Dispos"},{"key":"2025121604015400100_bib32","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/s41591-024-03330-x","article-title":"Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial","volume":"31","author":"Anderegg","year":"2025","journal-title":"Nat Med"},{"key":"2025121604015400100_bib33","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s44337-025-00241-9","article-title":"Exploring the impact of type 2 diabetes and glucose-lowering drugs on gut microbiome dynamics","volume":"2","author":"Tariq","year":"2025","journal-title":"Disc Med"},{"key":"2025121604015400100_bib34","doi-asserted-by":"publisher","first-page":"865","DOI":"10.2147\/DMSO.S451129","article-title":"Effects of glucagon-like peptide-1 receptor agonists on gut microbiota in dehydroepiandrosterone-induced polycystic ovary syndrome mice: compared evaluation of liraglutide and semaglutide intervention","volume":"17","author":"Xiong","year":"2024","journal-title":"Diabetes Metab Syndr Obes"},{"key":"2025121604015400100_bib35","doi-asserted-by":"publisher","first-page":"123407","DOI":"10.1016\/j.lfs.2025.123407","article-title":"Butyrate increases cardiac output and causes vasorelaxation in a healthy porcine model","volume":"363","author":"Christensen","year":"2025","journal-title":"Life Sci"},{"key":"2025121604015400100_bib36","article-title":"Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associated with increasing effect on the gut microbiota in db\/db mice","author":"Wu","year":"2023","journal-title":"Front Endocrinol"},{"key":"2025121604015400100_bib37","doi-asserted-by":"publisher","first-page":"159234","DOI":"10.1016\/j.bbalip.2022.159234","article-title":"Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota","volume":"1867","author":"Deng","year":"2022","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"2025121604015400100_bib38","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1210\/clinem\/dgac210","article-title":"Cardiovascular benefits of Empagliflozin are associated with gut microbiota and plasma metabolites in type 2 diabetes","volume":"107","author":"Deng","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2025121604015400100_bib39","first-page":"2025","article-title":"Reduced abundance of Fusobacterium signifies cardiovascular benefits of sodium glucose cotransporter 2 inhibitor in type 2 diabetes: a single arm clinical trial","volume":"16","author":"Yang","year":"2025","journal-title":"Front Pharmacol"},{"key":"2025121604015400100_bib40","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.diabet.2019.11.005","article-title":"Effects of 12-week treatment with dapagliflozin and gliclazide on faecal microbiome: results of a double-blind randomized trial in patients with type 2 diabetes","volume":"46","author":"van Bommel","year":"2020","journal-title":"Diabetes Metab"},{"key":"2025121604015400100_bib41","article-title":"Effects of SGLT2 inhibitors on modulating protein-bound uremic toxins and gut microbiota in pre-dialysis CKD patients: a matched case-control study","volume":"360","author":"Hsu","year":"2025","journal-title":"Kidney"},{"key":"2025121604015400100_bib42","doi-asserted-by":"publisher","first-page":"329","DOI":"10.4330\/wjc.v14.i6.329","article-title":"Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes","volume":"14","author":"Singh","year":"2022","journal-title":"World J Cardiol"},{"key":"2025121604015400100_bib43","doi-asserted-by":"publisher","first-page":"e34978","DOI":"10.1097\/MD.0000000000034978","article-title":"GLP-1 receptor agonists modulate blood glucose levels in T2DM by affecting Faecalibacterium prausnitzii abundance in the intestine","volume":"102","author":"Liang","year":"2023","journal-title":"Medicine"},{"key":"2025121604015400100_bib44","volume":"14","author":"Favero","year":"2022","journal-title":"Postbiotics and Kidney Disease Toxins"},{"key":"2025121604015400100_bib45","doi-asserted-by":"publisher","first-page":"106504","DOI":"10.1016\/j.jinf.2025.106504","article-title":"Faecal microbiota transplant to ERadicate gastrointestinal carriage of Antibiotic-Resistant organisms (FERARO): a feasibility randomised controlled trial","volume":"91","author":"Merrick","year":"2025","journal-title":"J Infect"},{"key":"2025121604015400100_bib46","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2025-335600","article-title":"Toxic microbiome and progression of chronic kidney disease: insights from a longitudinal CKD-microbiome study","author":"Szeto","year":"2025","journal-title":"Gut"}],"container-title":["Clinical Kidney Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ckj\/advance-article-pdf\/doi\/10.1093\/ckj\/sfaf351\/65289977\/sfaf351.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ckj\/article-pdf\/18\/12\/sfaf351\/65289977\/sfaf351.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ckj\/article-pdf\/18\/12\/sfaf351\/65289977\/sfaf351.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:02:03Z","timestamp":1765875723000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ckj\/article\/doi\/10.1093\/ckj\/sfaf351\/8323136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":46,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ckj\/sfaf351","relation":{},"ISSN":["2048-8505","2048-8513"],"issn-type":[{"value":"2048-8505","type":"print"},{"value":"2048-8513","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,11,14]]},"article-number":"sfaf351"}}